Abstract
A homology model of the p110alpha catalytic subunit of PI3Kalpha was generated from the p110gamma crystal structure. Using this model, an isonicotinic scaffold was designed for chemically exploring the PI3Kalpha and gamma binding sites. A focused library of derivatives was synthesized and tested. The morpholine acids 5a and 5b proved to be the most potent analogs.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Binding Sites
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Catalytic Domain
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Class II Phosphatidylinositol 3-Kinases
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Class Ib Phosphatidylinositol 3-Kinase
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Crystallography, X-Ray
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / chemistry
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Isoenzymes / metabolism
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Isonicotinic Acids / chemistry*
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Isonicotinic Acids / metabolism*
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Isonicotinic Acids / pharmacology
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Models, Molecular
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Morpholines / chemistry
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Phosphatidylinositol 3-Kinases / chemistry*
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Protein Binding
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Pyridines / chemistry
Substances
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Isoenzymes
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Isonicotinic Acids
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Pyridines
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morpholine
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Class II Phosphatidylinositol 3-Kinases
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Class Ib Phosphatidylinositol 3-Kinase
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pyridine